Project Summary Up to 95% of premature infants undergo red blood cell (RBC) transfusion while in the intensive care unit, yet it is unknown whether more restrictive or more liberal transfusions will lead to optimal brain development. The Transfusion of Prematures (TOP) Trial is a multi-center study funded by the NHLBI and supported by the NICHD Neonatal Research Network (NRN). The primary objective of the TOP Trial is to assess survival and rates of neurodevelopmental impairment at 22-26 months corrected age in extremely low birth weight (ELBW) infants that are randomized to either liberal or restrictive RBC transfusion thresholds. The trial began enrollment in December 2012 and reached the target sample size of 1,824 infants on time in April 2017. Although major deficits in motor and cognitive function may be detected at 22-26 months of age, these infants are too young to assess cognitive, behavioral, and coordination skills that, if impaired, can lead to problems with academic skills, motor performance or adaptive functioning in home or school environments, conditions that are far more prevalent in this population and create substantial morbidity for the children and their families. Because optimal transfusion management is a critical knowledge gap in neonatology, the currently proposed TOP 5 Study will assess functional neurodevelopmental outcomes of infants randomized to two different transfusion thresholds in the TOP Trial at 5 years corrected age. The TOP 5 Study Clinical Coordinating Center (CCC) is led by Co-PIs Dr. Peg Nopoulos, who has a ten-year history of studying the outcomes of premature infants exposed to liberal or restrictive transfusion, and Dr. Sara DeMauro, who has extensive experience conducting multicenter outcomes studies in collaboration with the NICHD NRN and the Data Coordinating Center (DCC) at RTI International. The DCC PI Dr. Abhik Das also leads the DCC for the NICHD NRN. The NRN has a superb track record in school-age outcomes research and history of productive collaboration with NHLBI. Thus, the TOP 5 Study has been thoughtfully designed to leverage existing successful research infrastructure, relationships, and resources in order to reduce redundancy and ensure success. The results of the TOP 5 study will provide evidence about which approach to neonatal transfusion (liberal or restrictive) minimizes damage to vulnerable neuronal circuits and, in turn, which transfusion strategy will improve both short and long-term outcomes for these vulnerable premature infants.